This is a renewal application of our 17th-year program (CA-40081) focusing on the total synthesis of cyclic peptide and depsipeptides with potent regulation of cell proliferation. Our studies have focused on 2 classes of natural products the didemnin/tamandarin depsipeptides from marine ascidians (tunicates) and the ustiltoxin/phomopsin heterodetic peptides of plant origin. Our approach develops total synthesis of families of natural products as tools for SAR and proteomic analyses. Our previous program has considerably advanced the synthetic chemistry of the tunicate metabolites and established unequivocally the structural similarity and biological activity of didemnin/tamandarin depsipeptides. New initiatives in this area will investigate the subpicomolar immunosuppressive activity of didemnin M and tamandarin M. Probe molecules designed on the tamandarin scaffold will be synthesized using advanced routes for biochemical investigations. Second generation fluorescent and affinity analogs of the tamandarins, are being prepared to untangle the relationships among the different types of activity. In vivo cell analyses have been combined with a rigorous proteomics approach to elucidate the molecular receptors for these depsipeptides. Using a refined approach, we continue our efforts towards understanding marine natural products by developing a comprehensive analysis of the activity, target and synthesis of an entire class of natural products. In a second set of studies, we have applied our class based approach to a set of tubulin regulators, the ustiloxins and phomopsins. We have demonstrated the ability to achieve facile syntheses of the ustiloxins, and now offer a sound platform for development of accurate methods for analog and congener preparation. Ongoing studies are now underway to transfer the knowledge gained through our analogs and derivatives to provide a comprehensive model for the SAR and biological activities of these heterodetic peptides.